Neostigmine and alpha-2 agonists as additives for neuraxial
blockade
a.o.Univ.Prof.Dr.Astrid Chiari
University of Vienna, Austria
Transmission of pain
from peripheral tissues to higher centres in the brain is modulated in the
dorsal horn of the spinal cord. Incoming messages can be enhanced or attenuated
by various transmitters derived from either primary afferent A delta and C
fibers, interneurons or descending bulbospinal fibers. After noxious
stimulation, excitatory neurotransmitters are released from afferent fibers.
Compensatory inhibitory neurotransmitters include (besides many others):
norepinephrine and acetylcholine. Thus, an interplay between excitatory and
inhibitory spinal neuronal systems will determine the message delivered to
higher levels of the central nervous system. Increased understanding in spinal
processing of pain has lead to development of specific drugs that inhibit pain
transmission without motor blockade. This review describes the experimental
background and the clinical use of neuraxial alpha-2-adrenergic agonists and
neostigmine administered alone or with other drugs.
Pain and systemic
opioids trigger the release of endogenous norepinephrine (NE) from bulbospinal
descending neurons, which in turn stimulates postsynaptic alpha 2 adrenoceptors
in the spinal cord to produce analgesia. Intrathecal injection of the alpha 2
adrenergic agonist, clonidine, mimics this effect of NE and produces analgesia
in animals and humans. Spinal alpha 2 adrenergic mediated antinociception also
involves a cholinergic interaction, since administration of clonidine results
in increased acetylcholine concentration in sheep and in humans.1
Clonidine was proven to have a higher analgesic potency after neuraxial than
after systemic administration and in volunteers, a concentration of clonidine
in CSF producing a 95% maximal analgesia to a noxious stimulus in the lower
extremity (130 ng/ml) has been established.2
Stimulation of
postsynaptic alpha 2 adrenoceptors in the brainstem and in the
intermediolateral column of the spinal cord decreases sympathetic outflow,
which causes bothersome side effects, primarily hypotension and bradycardia.
Sedation has also been observed with the administration of alpha 2 adrenergic
agonists, due to actions in the locus coeruleus. In contrast, neuraxial
clonidine has not been associated with respiratory depression or motor
blockade.3
Administered
intrathecally by itself, clonidine fails to produce reliable surgical
anesthesia despite a high dose (450 µg). In contrast, intrathecal clonidine
(150-450 µg) provides dose dependent postoperative analgesia for women
following caesarean section4, lasting up to 14 hours, but associated
with severe intense sedation and hemodynamic depression. 50-200 µg spinally
injected clonidine have been successfully used as the sole analgesic during
first stage of labor, although the larger doses were accompanied by
hypotension.5 Synergistic interactions between spinal alpha 2
adrenergic agonists and opioids have been observed in rodents, but this does not
seem to be also true in humans. The ED 50 of epidural clonidine in
postoperative analgesia is markedly reduced in humans when combined with
fentanyl , but this interaction is only additive, not synergistic. When
sufentanil and clonidine are combined spinally during labor in small as well as
in large doses, duration of analgesia is prolonged, but the incidence of
hypotension limits the clinical usefulness in this setting.6
Epidural clonidine by
itself produces dose-dependent intra- and postoperative analgesia and has been
successfully used as the sole analgesic agent during and after major abdominal
surgery, where it provided more efficient postoperative analgesia than epidural
bupivacaine.7
In clinical practice,
however, intrathecal or epidural clonidine is mostly administered in
conjunction with local anesthetics. Addition of 150 µg clonidine to spinal or
epidural bupivacaine improves the quality and increases the duration of postoperative and obstetric analgesia.3
When clonidine is added to local anesthetics, a decrease in blood pressure 20%
off baseline must be expected due to the additional sympathetic blockade caused
even by small doses of clonidine. Whereas the addition of large doses of
clonidine (75-150 µg) to spinal local anesthetics reduces heart rate and blood
pressure8, small doses of clonidine (15 µg) combined with
intrathecal ropivacaine did not show
such side effects while producing anesthesia suitable for ambulatory surgery.
Clonidine 1-2 µg/kg
has been added to caudal bupivacaine and ropivacaine for pediatric hernia
repair and increased duration of analgesia, but recent reports of respiratory
depression question its safety in preterm infants.
Since intrathecal
alpha 2 adrenergic agonists produce analgesia through a different mechanism than
intrathecal opioids, patients suffering from chronic pain tolerant to opioids
can be provided with analgesia by neuraxial alpha 2 adrenergic agonists alone
or combined with opioids. Especially neuropathic pain can be treated very
effectively with spinal and epidural clonidine due to a different physiology in
the spinal cord in these pain states. However, published experience with this
small group of patients is too limited to give common dose recommendations.
Spinal alpha 2
adrenergic receptor activation - either through endogenous NE or spinally
administered clonidine - involves
spinal cholinergic pathways and transmitters to produce analgesia.1
Spinally administered neostigmine causes analgesia in animals and humans by
preventing the breakdown of synaptically released acetylcholine, which acts on
muscarinic and also nicotinc receptors in the spinal cord. Neostigmine is a
quaternary amine, unable to cross the blood-brain barrier and therefore has to
be administered spinally in order to reach the target organ, the spinal cord.
When injected
intrathecally in volunteers, neostigmine produces dose dependent analgesia but
also severe nausea and vomiting, probably due to cephalad spread and action in
the brainstem.9 This side effect can be reduced by injecting the
drug in a hyperbaric solution and keeping the head of the bed elevated. Since
alpha adrenergic agonists and neostigmine act through the same mechanism,
additive analgesic enhancement has been observed with the combination of
intrathecal neostigmine and epidural clonidine in volunteers. In addition,
neostigmine increases sympathetic outflow, thus counteracting the hypotension
of i.t. local anesthetics and clonidine.
In a volunteer study,
the addition of 6.25-50 µg neostigmine to spinal bupivacaine revealed a high
incidence in nausea and vomiting and a delayed recovery from anesthesia.10
In the clinical setting, intrathecal neostigmine (25-75µg) coadministerd with
bupivacaine for spinal anesthesia revealed a dose-independent reduction in
postoperative rescue analgesic consumption, but also a dose-independent
increase in the need for antiemetic treatment.11 In obstetrics,
intrathecal neostigmine (5-20 µg) alone failed to show any analgesic effect by
itself, but it increased the analgesia from i.t. sufentanil.
These studies suggest
that intrathecal neostigmine alone is unlikely to produce complete
postoperative or labor analgesia but it might become a future adjunctive spinal
analgesic in very small doses.
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